L-carnitine plays a significant role in .beta.-oxidation of fatty acids and, as a result, has created an increasing demand for this compound in medicine (see, e.g., Bremer, Trends Biochem. Sci. 2:207-9, 1977). Such demand has led to the development of numerous procedures lbr production of L-carnitine, including its isolation from natural sources, synthetic chemical procedures (such as resolution of racemic mixtures of DL-carnitine), and transformation by enzymes and microorganisms.
A number of chemical methods for the synthesis of DL-carnitine are known. For example, U.S. Pat. No. 3,135,788 is directed to the preparation of DL-carnitine hydrochloride in which epichlorohydrin is first treated with trimethylamine to provide 1-chloro-2-hydroxy-4-(trimethylammonio)butane. Subsequent displacement of chloride by treatment with potassium cyanide produces the corresponding cyano compound which, upon acidic hydrolysis, yields DL-carnitine. A similar strategy was employed in U.S. Pat. No. 4.070,394 where the chloride of epichlorohydrin was initially displaced by trimethylamine and the product thus obtained treated with various metal cyanides to yield 1-cyano-2-hydroxy-4-(trimethylammonio)butane, which is then converted to DL-carnitine by hydrolysis.
The discovery of adverse effects of D-carnitine, and the questionable therapeutic effectiveness of the racemic mixture of DL-carnitine, has driven the search for a practical and economically efficient preparation of L-carnitine. To this end, optically pure L-carnitine has now been prepared by resolution from its racemic mixture. For example, U.S. Pat. No. 3,151,149 is directed to such a resolution by recrystallization using D-(+)-camphor-10-sulfonic acid. The synthesis of L-carnitine from optically pure precursors resolved from their respective racemic mixtures has also been reported. For example, racemic mixtures of 1-chloro-2-hydroxy-4-(trimethylammonio)butane have been resolved using L-(+)-tartaric acid, and the resulting enantiomerically pure chlorobutane chemically transformed to L-carnitine (Voeffray et. al., Helv. Chim. Acta 70:2058-64, 1987).
Optically pure L-carnitine has also been prepared from chiral compounds including (R)-4-chloro-3-hydroxybutyrate. For example, a chemomicrobiological synthesis of L-carnitine has been reported (Zhou et al., J. Amer. Chem. Soc. 105:5925-26, 1983) wherein optically pure (R)-4-chloro-3-hydroxybutyrate was prepared from ethylacetoacetate by reduction by baker's yeast, and then converted to L-carnitine by standard methods. Another enzymatic synthesis of (R)-4-chloro-3-hydroxybutyrate employing a coupled enzyme system of glucose dehydrogenase and alcohol dehydrogenase has also been reported (Wong et al., J. Amer. Chem. Soc. 107: 4028-31, 1985).
Despite the availability of L-carnitine, existing methods for its production are indirect, laborious, and economically prohibitive. Accordingly, there is a need in the art for a direct and efficient route to optically pure L-carnitine. The present invention fulfills this need, and provides further related advantages.